In a Profile of optogenetics pioneer Karl Deisseroth, John Colapinto (2015)[i] provided a concise description of the physical brain and the activities of its parts:

“For much of the history of brain research, it has been nearly impossible to accurately test ideas about how the brain works. “When we have the complexity of any biological system—but particularly the brain—where do you start?” Deisseroth says. Among scientists, he is best known for his development of optogenetics, a technology that renders individual, highly specific brain cells photosensitive and then activates those cells using flashes of light delivered through a fibre-optic wire. Optogenetics has given researchers unprecedented access to the workings of the brain, allowing them not only to observe its precise neural circuitry in lab animals but to control behavior through the direct manipulation of specific cells. Deisseroth, one of the rare neuroscientists who are also practicing psychiatrists, has made mental illness a major focus of his optogenetic research. Other scientists around the world are using the method to investigate some of the most stubborn riddles of neuroscience, including the fundamental question of how the physical brain—the nearly hundred billion neurons and their multitudinous connections—gives rise to the mind: thought, mood, behavior, emotion.

In the late seventeen-hundreds, the Italian physician Luigi Galvani noticed that static electricity could induce a dead frog’s leg to move. For the first time, scientists understood that the nervous system operates under the influence of electrical activity. But it was not until the nineteen-twenties that a Swiss researcher, Walter R. Hess, using implanted wires to stimulate the brains of cats, showed that emotion and behavior also arise from electrical impulses in the brain. By stimulating various brain regions, Hess induced different reactions: for example, a cat could be made to show the defensiveness it might otherwise display when confronted by a dog.

In the nineteen-fifties, a Spanish physiologist at Yale, José Manuel Rodriguez Delgado, conducted experiments with electrodes implanted in the brains of human subjects, using a device he had invented, called a “stimoceiver,” a half-dollar-size electrode operated by remote control. Delgado used the stimoceiver in some twenty-five patients, most of them epileptics and schizophrenics in a Rhode Island mental hospital, and reported that it was “possible to induce a large variety of responses, from motor effects to emotional reactions and intellectual manifestations.” The experiments sparked outrage when they were made public, and Delgado returned to Spain.

The ethical concerns inherent in implanting electrodes in human brains gave way, in the early nineteen-nineties, to the adoption of a wholly noninvasive brain-imaging technology: functional magnetic resonance imaging, or fMRI. It was instrumental in bolstering the theory that the brain is divided into discrete regions responsible for different aspects of behavior. The technology uses powerful magnets to detect changes in blood flow in the brain in subjects who are exposed to various stimuli—images, sounds, thoughts. Activated regions can be presented on a screen as luminous blobs of color. But fMRI has severe limitations. There is a time lag, and different neuronal events that happen a second or more apart can blur together when the excited area appears onscreen—a liability in studying an organ that works at millisecond speed. Nor can fMRI reveal what brain cells are actually doing. The technique registers activity only at the scale of hundreds of thousands of neurons, and a lit-up area might represent any number of neural processes. Given this lack of precision, even some of fMRI’s defenders offer faint praise. Nancy Kanwisher, of M.I.T., who has done groundbreaking work to isolate a brain region implicated in face recognition, says, “The real miracle of fMRI is that we ever see anything at all.”

To analyze the role of small groups of neurons, scientists have relied on a method not unlike the one that Hess used with his cats: stimulating targeted brain areas, in experimental animals, with thin electrodes. Because electrodes spread current through brain tissue, stimulating activity in unwanted areas, researchers use a drug to suppress neural activity. But the method is cumbersome and time-consuming.

In 2005, Deisseroth published his first paper on what came to be known as optogenetics. Because the technology permits researchers not only to trigger the activity of cells at the speed that the brain actually works but also to target cells in regions, like the amygdala, where there are mixed populations of hundreds of kinds of cells, optogenetics offers a previously unthinkable level of experimental precision. At present, optogenetics can be used only on animals like mice and rats, whose brain functions associated with elemental emotions, like fear and anxiety and reward, are similar to those in humans. But Deisseroth’s work with patients like Sally, whose VNS implant allows him to control emotions and behavior, hints at what may one day be possible.

Christof Koch, the chief scientific officer of the Allen Institute for Brain Science, in Seattle, calls optogenetics one of the most momentous developments in neuroscience in the past hundred and sixty years—from the original dye-staining of cell types, in the late nineteenth century, through the use of electrodes, in the fifties and sixties, to the advent of fMRI. “Optogenetics is the fourth wave,” Koch told me. “I can now begin to intervene in the network of the brain in a very delicate, deliberate, and specific way.” Experiments have shed light on many brain functions, including learning, memory, metabolism, hunger, sleep, reward, motivation, fear, smell, and touch.”